Actin mutations are one cause of congenital fibre type disproportion

Authors

  • Nigel G. Laing PhD,

    Corresponding author
    1. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute and Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia
    • Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, 4th Floor, ‘A’ Block, Queen Elizabeth II Medical Centre, Nedlands, Western Australian 6009, Australia
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  • Nigel F. Clarke MB, ChB,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
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  • Danielle E. Dye BSc, Hons,

    1. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute and Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia
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  • Khema Liyanage BSc, Hons,

    1. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute and Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia
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  • Kendall R. Walker BSc, Hons,

    1. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute and Centre for Medical Research, West Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia
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  • Yasuaki Kobayashi MD,

    1. Department of Pediatrics, Ohtawara Red Cross Hospital, Ohtawara, Tochigi
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  • Shuichi Shimakawa MD, PhD,

    1. Department of Pediatrics, Osaka Medical College Hospital, Takatsuki, Osaka, Japan
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  • Tohru Hagiwara MD, PhD,

    1. Department of Pediatrics, Osaka Medical College Hospital, Takatsuki, Osaka, Japan
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  • Robert Ouvrier MD,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
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  • John C. Sparrow D Phil,

    1. Department of Biology, University of York, York, United Kingdom
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  • Ichizo Nishino MD, PhD,

    1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi-cho, Kodaira, Tokyo, Japan
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  • Kathryn N. North MD, MBBS,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
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  • Ikuya Nonaka MD, PhD

    1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi-cho, Kodaira, Tokyo, Japan
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Abstract

We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1. Ann Neurol 2004

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